Cyanoacrylate compositions comprising an antimicrobial agent

ABSTRACT

Disclosed are cyanoacrylate compositions comprising a compatible antimicrobial agent and, in particular, a compatible iodine containing antimicrobial agent. These compositions provide for in situ formation of an antimicrobial polymeric cyanoacrylate film on mammalian skin.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation-in-part of U.S. Ser. No. 08/781,409filed Jan. 10, 1997, now U.S. Pat. No. 5,684,042 which issued on Nov. 4,1997, which application is incorporated herein by reference in itsentirety.

BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention is directed to cyanoacrylate prepolymer compositionscomprising a compatible antimicrobial agent and, in particular, aniodine containing antimicrobial agent. These compositions provide for insitu formation of antimicrobial polymeric cyanoacrylate films onmammalian skin which films are useful as wound dressings, woundbandages, surgical incise drapes, wound closure materials which replaceor are an adjunct to sutures, and the like.

This invention is also directed to kits of parts comprising suchprepolymer compositions and an applicator means for applying thecomposition to mammalian skin.

References

The following publications, patent applications and patents are cited inthis application as superscript numbers:

¹ Hawkins, et al., Surgical Adhesive Compositions, U.S. Pat. No.3,591,676, issued Jul. 6, 1971

² Halpern, et al., Adhesive for Living Tissue, U.S. Pat. No. 3,667,472,issued Jun. 6, 1972

³ McIntire, et al., Process for the Preparation ofPoly(α-Cyanoacrylates), U.S. Pat. No. 3,654,239, issued Apr. 4, 1972

⁴ Barley, et al., Methods for Treating Non-Suturable Wounds by Use ofCyanoacrylate Adhesives, International Patent Application PublicationNo. WO 93/25196, published Dec. 23, 1993

⁵ Barley, et al., Methods for Treating Suturable Wounds by Use ofSutures and Cyanoacrylate Adhesives, U.S. Pat. No. 5,254,132, issuedOct. 19, 1993

⁶ Barley, et al., Methods for Reducing Skin Irritation From ArtificialDevices by Use of Cyanoacrylate Adhesives, U.S. Pat. No. 5,653,789,issued Aug. 5, 1997

⁷ Rabinowitz, et al., Method of Surgically Bonding Tissue Together, U.S.Pat. No. 3,527,224, issued Sep. 8, 1970

⁸ Kronenthal, et al., Surgical Adhesives, U.S. Pat. No. 3,995,641,issued Dec. 7, 1976

⁹ Davydov, et al., Medical Adhesive, U.S. Pat. No. 4,035,334, issuedJul. 12, 1977

¹⁰ Waniczek, et al., Stabilized Cyanoacrylate Adhesives ContainingBis-Trialkylsilyl Esters of Sulfuric Acid, U.S. Pat. No. 4,650,826,issued Mar. 17, 1987

¹¹ Askill, et al., "Methods for Draping Surgical Incision Sites" U.S.Pat. No. 5,730,994 which issued on Mar. 24, 1998 filed Jan. 10, 1997

¹² Greff, et al., Cyanoacrylate Adhesive Compositions, U.S. Pat. No.5,480,935, issued Jan. 2, 1996

¹³ Hagen, et al., "A Comparison of Two Skin Preps Used in CardiacSurgical Procedures", AORN Journal, 62(3):393-402 (1995)

¹⁴ Ritter, et al., "Retrospective Evaluation of an Iodophor-incorporatedAntimicrobial Plastic Adhesive Wound Drape", Clinical Orthopedics andRelated Research, pp. 307-308 (1988)

¹⁵ Osuna, et al., "Comparison of an Antimicrobial Adhesive Drape andPovidone-Iodine Preoperative Skin Preparation in Dogs", VeterinarySurgery, 21(6):458-462 (1992)

¹⁶ O'Sullivan, et al., High Viscosity Cyanoacrylate AdhesiveCompositions, and Process for Their Preparation, U.S. Pat. No.4,038,345, issued Jul. 26, 1977

¹⁷ Beller, et al., Process for the Preparation ofIodine-Polyvinylpyrrolidone by Dry Mixing, U.S. Pat. No. 2,706,701,issued Apr. 19, 1955

.sup.˜ Hosmer, Process of Stabilizing Polyvinylpyrrolidone, U.S. Pat.No. 2,826,532, issued Mar. 11, 1958

¹⁹ Siggin, Preparation of Iodine Polyvinylpyrrolidone Adducts, U.S. Pat.No. 2,900,305, issued Aug. 18, 1958

²⁰ Joyner, et al., Plasticized Monomeric Adhesive Compositions andArticles Prepared Therefrom, U.S. Pat. No. 2,784,127, issued Mar. 5,1957

²¹ Columbus, et al., Adhesive Cyanoacrylate Compositions with ReducedAdhesion to Skin, U.S. Pat. No. 4,444,933, issued Apr. 24, 1984

²² Leung, et al., Biocompatible Monomer and Polymer Compositions, U.S.Pat. No. 5,328,687, issued Jul. 12, 1994

²³ Byram, et al., Use of Cyanoacrylate Adhesive Compositions to InhibitAcute Radiation-Induced Skin Damage, U.S. Pat. No. 5,554,365, issuedSep. 10, 1996.

²⁴ Leplyanin, "Medical and Surgical Adhesive Composition and Process forIts Preparation", International Application Publication No. WO 96/23532published Aug. 8, 1996

²⁵ Tighe, et al., "Use of Cyanoacrylate Adhesives For Providing AProtective Barrier Film For The Skin", U.S. Pat. No. 5,580,565, issuedon Dec. 3, 1996.

²⁶ Cardarelli, et al., "Film Forming Antimicrobial Material", U.S. Pat.No. 4,374,126, issued Feb. 15, 1983

²⁷ Barnes, "Biocidal Complex and Dressing Formed Therefrom", U.S. Pat.No. 5,051,256, issued Sep. 24, 1991

²⁸ Dell, "Film-Forming Composition Containing an Antimicrobial Agent andMethods", U.S. Pat. No. 4,542,012, issued Sep. 17, 1985

²⁹ Brink, et al., "Film-Forming Emulsion Containing Iodine and Methodsof Use", U.S. Pat. No. 5,173,291, issued Dec. 22, 1992

³⁰ Khan, et al., "Preparation of a Skin Surface for a SurgicalProcedure", U.S. Pat. No. 5,547,662, issued Aug. 20, 1996

³¹ Blum, et al., In vitro Determination of the Antimicrobial Propertiesof Two Cyanoacrylate Preparations, J. Dent. Res., 54(3):500-503 (1975)

All of the above publications, patent applications and patents areherein incorporated by reference in their entirety to the same extent asif each individual publication, patent application or patent wasspecifically and individually indicated to be incorporated by referencein its entirety.

2. State of the Art

Cyanoacrylate esters have been disclosed for a variety of topical useson mammalian skin including use as a replacement or adjunct for suturesor staples in closing the dermal layer of an incision aftersurgery.¹,2,5 Other disclosed topical uses include use as a hemostat³,use in covering small non-suturable wounds on skin surfaces⁴, use ininhibiting surface skin irritation arising from friction between theskin surface and artificial devices such as tapes, prosthetic devices,casts, etc.⁶ and use in inhibiting acute radiation-induced skindamage.²³ Still another topical use of cyanoacrylate esters is its usein the in situ formation of a surgical incise drape.¹¹ In each case,when topically applied to mammalian skin, the cyanoacrylate rapidlypolymerizes, typically within a minute, to form a coherent polymericfilm which strongly adheres to the skin.

Cyanoacrylate esters suggested for such uses include the followingstructures: ##STR1## wherein R is an alkyl or other suitablesubstituent. Such cyanoacrylate esters are disclosed in, for example,U.S. Pat. Nos. 3,527,224; 3,591,676; 3,667,472; 3,995,641; 4,035,334;and 4,650,826.¹,2,7-10

Cyanoacrylate ester compositions for topical skin application typicallyare formulated to contain both a plasticizer to enhance flexibility ofthe resulting polymeric film and a polymerization inhibitor to avoidpremature polymerization of the composition. When employed topically onmammalian skin, Greff et al.¹² disclose that the cyanoacrylatecomposition preferably employs from about 50 to about 500 ppm sulfurdioxide as the polymerization inhibitor and from about 18-25 weightpercent of a biocompatible plasticizer such as dioctyl phthalate.

Notwithstanding the beneficial properties associated with suchcyanoacrylate ester compositions and their suitability for topicalapplications, these compositions do not possess a sufficiently broadspectrum of antimicrobial activity including activity against microbialspores³¹ and, accordingly, cannot assure reductions in microbialpopulations on mammalian skin surface either under or adjacent apolymeric cyanoacrylate film formed in situ on the skin.

Many of the uses of cyanoacrylate ester compositions enumerated abovewould, however, significantly benefit by a broad spectrum ofantimicrobial property in the polymer film. For instance, covering smallnon-suturable wounds on skin surfaces with a polymeric cyanoacrylatefilm having a broad spectrum of antimicrobial activity would mitigateagainst possible wound infection. Likewise, when used as a surgical(incise) drape, such films would reduce microbial populations under andadjacent the drape including those at the incision site and,accordingly, would reduce the risk of post-operative infection. Such isthe basic premise of commercial surgical drapes containing anantimicrobial agent impregnated directly into the drape or an adhesivelayer attached thereto where it was hoped that this agent would bereleased onto the skin surface to inhibit microbial growth.¹³,14 Osuna,et al.¹⁵ report, however, that when the antimicrobial agent isincorporated into the adhesive layer, the adhesive does not releasesufficient amounts of the impregnated agent to be, by itself,antimicrobial. Without being limited to any theory, it is believed thatthe antimicrobial agent is too strongly bound onto/into the adhesive tobe released onto the skin and/or that there is insufficient skin surfacecontact between the adhesive and the skin to effect release of asufficient amount of antimicrobial agent.

As noted above, cyanoacrylate esters do not possess broad antimicrobialactivity and, accordingly, incorporation of broad antimicrobialproperties into the cyanoacrylate polymeric film necessitates, ofcourse, that an antimicrobially effective amount of a broad spectrumantimicrobial agent be incorporated into the prepolymeric cyanoacrylatecomposition and that sufficient amounts of this agent be released fromthe polymeric cyanoacrylate film onto the skin to achieve anantimicrobial effect. The incorporation of such an antimicrobial agentinto the cyanoacrylate composition is problematic at best becauseseveral disparate criteria must be simultaneously met. First, theantimicrobial agent must be soluble or dispersible in the cyanoacrylatecomposition at the concentrations necessary to effect antimicrobialproperties. Second, the antimicrobial agent employed must not causepremature polymerization of the cyanoacrylate ester composition. Third,the antimicrobial agent employed must not prevent in situ polymerizationof the cyanoacrylate composition when applied to the skin. Fourth, theantimicrobial agent must be compatible with the intended use of thepolymeric film by not inhibiting formation of a flexible, durable film.Fifth, the impregnated antimicrobial agent must be released from thepolymerized film in situ on the patient's skin in sufficient amounts tobe antimicrobial.

Because of these disparate properties, many conventional antimicrobialagents are unsuitable for use in the prepolymeric compositions of thisinvention and typically the prior art has incorporated an antimicrobialagent into a solution or emulsion of the formed polymer or by directmixing in the polymer melt (Mixon, U.S. Pat. No. 5,069,907).

When the antimicrobial agent is incorporated into the solution emulsion,after placement on the patient's skin and subsequent evaporation of thesolvent, a polymer film is formed which film is permeated with theantimicrobial agent.²⁶,28-29 Since the polymer is preformed prior toapplication to the skin, these solutions/emulsions reduce the effectiveadherence of the polymer film to the skin and, accordingly, could leadto premature lifting or removal of the film from the skin. Moreover, theuse of water and other solvents in the emulsion or solution can lead toslow drying times for the film with the concurrent difficulty indetermining when or if the solvent has evaporated sufficiently toprovide a polymer film on the patient's skin.

In view of the clear benefits associated with the incorporation of anantimicrobial agent directly into the monomeric cyanoacrylatecomposition, there is an ongoing need to formulate a cyanoacrylatecomposition comprising a broad spectrum antimicrobial agent.

SUMMARY OF THE INVENTION

This invention is directed to cyanoacrylate ester compositionscomprising an antimicrobially effective amount of a complex of iodinemolecules with a biocompatible polymer. These compositions provide forin situ formation of an antimicrobial polymeric cyanoacrylate film onmammalian skin. The specific antimicrobial iodine complex employed iscompatible with the cyanoacrylate composition insofar as theantimicrobial complex neither causes premature polymerization norprevents polymerization of the monomer, rather a flexible and durablepolymeric film is formed in situ on mammalian skin by this composition.Moreover, in vitro assays evidence that the antimicrobial agent isreleased from the polymeric film in antimicrobially effective amountsthereby imparting antimicrobial properties to the polymeric film.

Accordingly, in one of its composition aspects, this invention isdirected to an antimicrobial cyanoacrylate composition which comprises:

(a) a polymerizable cyanoacrylate ester; and

(b) an antimicrobially effective amount of a complex of iodine moleculeswith a biocompatible polymer.

Preferably, the polymerizable cyanoacrylate ester is a polymerizablemonomer or reactive oligomer of a cyanoacrylate ester. Such monomers andreactive oligomers are sometimes referred to herein simply as"prepolymers" and, in monomeric form, are preferably represented byformula I: ##STR2## wherein R is selected from the group consisting of:alkyl of 1 to 10 carbon atoms,

alkenyl of 2 to 10 carbon atoms,

cycloalkyl groups of from 5 to 8 carbon atoms,

phenyl,

2-ethoxyethyl,

3-methoxybutyl,

and a substituent of the formula: ##STR3## wherein each R' isindependently selected from the group consisting of: hydrogen andmethyl, and R" is selected from the group consisting of:

alkyl of from 1 to 6 carbon atoms,

alkenyl of from 2 to 6 carbon atoms,

alkynyl of from 2 to 6 carbon atoms,

cycloalkyl of from 3 to 8 carbon atoms,

aralkyl selected from the group consisting of benzyl, methylbenzyl andphenylethyl,

phenyl, and

phenyl substituted with 1 to 3 substituents selected from the groupconsisting of hydroxy, chloro, bromo, nitro, alkyl of 1 to 4 carbonatoms, and alkoxy of from 1 to 4 carbon atoms.

More preferably, in the cyanoacrylate esters of formula I, R is alkyl offrom 2 to 10 carbon atoms and still more preferably alkyl of from 4 to 8carbon atoms. Even more preferably, R is butyl, pentyl or octyl and mostpreferably, R is n-butyl.

Antimicrobial complexes of iodine molecules with a biocompatible polymerpreferably include polyvinylpyrrolidone polymers which are also referredto under the common name of Povidone or PVP (commercially available fromBASF, Mt. Olive, N.J., USA), copolymers of vinylpyrrolidone and vinylacetate, copolymers of vinylpyrrolidone and vinyl acetate cross-linkedwith polyisocyanates, copolymers of vinylpyrrolidone and vinylfunctionalities, polymers of pyrrolidone²⁷ and the like. Preferably, theiodine containing polymer is Povidone Iodine which is commerciallyavailable from a number of sources.

The antimicrobial cyanoacrylate compositions preferably further comprisean effective amount of a polymerization inhibitor and a biocompatibleplasticizer. The preferred polymerization inhibitor is sulfur dioxidewhich is preferably employed at from about 50 to about 500 ppm, andpreferably 200 to 500 ppm, based on the total weight of the compositionabsent the antimicrobial agent. The preferred biocompatible plasticizeris dioctyl phthalate which is preferably employed at from about 18 to 25weight percent based on the total weight of the composition absent theantimicrobial agent.

This invention is also directed to kits useful for applying theantimicrobial cyanoacrylate compositions described herein onto mammalianskin. In particular, such a kit of parts comprises (a) a containercomprising therein an antimicrobial prepolymeric composition asdescribed above and (b) an applicator means for applying the compositiononto mammalian skin.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

This invention is directed, in part, to cyanoacrylate compositionscomprising an antimicrobially effective amount of a compatible iodinecontaining antimicrobial agent. However, prior to discussing thisinvention in further detail, the following terms will first be defined.

Definitions

As used herein, the following terms have the following meanings:

The term "cyanoacrylate ester compositions" or "cyanoacrylatecompositions" refers to polymerizable formulations comprisingpolymerizable cyanoacrylate ester monomers and/or oligomers which, intheir monomeric form, are preferably compounds represented by formula Ias described above.

More preferably, in formula I, R is an alkyl group of from 2 to 10carbon atoms including, by way of example, ethyl, n-propyl, iso-propyl,n-butyl, isobutyl, sec-butyl, n-pentyl, iso-pentyl, n-hexyl, iso-hexyl,2-ethylhexyl, n-heptyl, n-octyl, nonyl, and decyl. More preferably, R isbutyl, pentyl or octyl and most preferably, R is n-butyl. Mixtures ofsuch compounds can also be employed.

Polymerizable cyanoacrylate esters are known in the art and aredescribed in, for example, U.S. Pat. Nos. 3,527,224; 3,591,676;3,667,472; 3,995,641; 4,035,334; and 4,650,826¹,2,7-10 the disclosuresof each are incorporated herein by reference in their entirety.

A particularly preferred cyanoacrylate ester for use in the invention isn-butyl-2-cyanoacrylate.

The polymerizable cyanoacrylate ester compositions described hereinrapidly polymerize in the presence of water vapor or tissue protein, andthe n-butyl-cyanoacrylate bonds human skin tissue without causinghistotoxicity or cytotoxicity.

Such polymerizable cyanoacrylate esters are sometimes referred to hereinas prepolymers and compositions comprising such esters are sometimesreferred to herein as prepolymer compositions.

The term "a biocompatible polymer" refers to polymers which, as iodinecomplexes (adducts), are compatible with in vivo applications ofcyanoacrylate ester compositions onto mammalian skin including humanskin. Representative polymers include polyvinylpyrrolidone, copolymerscomprising polyvinylpyrrolidone which is optionally crosslinked, and thelike. Suitable copolymers include copolymers of polyvinylpyrrolidone andvinyl acetate or other vinyl compounds which copolymers are optionallycrosslinked with a polyisocyanate. The molecular weight of thesepolymers is not critical with number average molecular weights rangingfrom about 10,000 to about 1,000,000 and preferably from 30,000 to300,000 being preferred.

The term "a complex of iodine molecules with a biocompatible polymer"refers to an antimicrobial complex formed by the addition of iodine (I₂)to the biocompatible polymer. Such complexes are well known in the artand the resulting complex typically comprises both available iodine andiodine anions. These complexes, on contact with mammalian skin, areantimicrobial apparently by providing for a source of antimicrobialiodine. In any event, such complexes are employed only as startingmaterials herein and, by themselves, do not form a part of thisinvention.

These complexes are sometimes referred to herein simply by the term"iodine/polymer complexes". Such iodine/polymer complexes aredistinguished from antibiotics which are naturally derived materialsfrom either bacteria or fungi and whose mode of action is to interferewith bacterial processes resulting in bacterial death. Contrarily, thecomplexes used in this invention are indiscriminate in destroying anymicrobes including fungi, viruses and bacteria apparently by release ofiodine into the microbes and, accordingly, are properly referred to asantimicrobial agents. Surprising, it has been found that of theantimicrobial agents tested, only the iodine/polymer complexes arecompatible in cyanoacrylate compositions. In fact, elemental (solid)iodine is incompatible with cyanoacrylate compositions because theaddition of elemental iodine renders such compositions non-polymerizableon mammalian skin. Accordingly, complexation of the iodine with thebiocompatible polymer is apparently essential for compatibility with thecyanoacrylate composition.

A preferred iodine/polymer complex for use in the compositions of thisinvention is a polyvinylpyrrolidone iodine complex which is describedin, for example, U.S. Pat. Nos. 2,706,701, 2,826,532 and 2,900,305¹⁷⁻¹⁹as well as at pp. 1106-1107 of the Tenth Edition of the Merck Index,Published by Merck & Co., Rahway, N.J., USA (1983) the disclosures ofwhich are incorporated herein by reference in their entirety. Thiscomplex is commercially available under the name "povidone-iodine" fromBASF, Mt. Olive, N.J., USA.

The term "biocompatible plasticizer" refers to any material which issoluble or dispersible in the cyanoacrylate composition, which increasesthe flexibility of the resulting polymer film coating on the skinsurface, and which, in the amounts employed, is compatible with the skinas measured by the lack of moderate to severe skin irritation. Suitableplasticizers are well known in the art and include those disclosed inU.S. Pat. Nos. 2,784,127²⁰ and 4,444,933²¹ the disclosures of both ofwhich are incorporated herein by reference in their entirety. Specificplasticizers include, by way of example only, acetyl tri-n-butyl citrate(preferably ˜20 weight percent or less), acetyl trihexyl citrate(preferably ˜20 weight percent or less) butyl benzyl phthalate, dibutylphthalate, dioctylphthalate, n-butyryl tri-n-hexyl citrate, diethyleneglycol dibenzoate (preferably ˜20 weight percent or less) and the like.The particular biocompatible plasticizer employed is not critical andpreferred plasticizers include dioctylphthalate.

The term "polymerization inhibitor" refers to conventional inhibitors ofcyanoacrylate esters including materials such as sulfur dioxide, glacialacetic acid, and the like. The polymerization inhibitor is typicallyemployed in amounts effective to inhibit polymerization untilapplication onto the mammalian skin. Because of its compatibility withtopical skin applications, the polymerization inhibitor is preferablysulfur dioxide which is preferably employed at from about 50 to 500 ppm,preferably 200 to 500 ppm, based on the total weight of the composition.Other preferred polymerization inhibitors include glacial acetic acid,free radical inhibitors (e.g., hydroquinones) and the like which can beused alone or in combination with SO₂.

The term "antimicrobial agent" refers to agents which destroy microbes(i.e., bacteria, fungi, viruses and microbial spores) thereby preventingtheir development and pathogenic action.

Compositions

This invention is based on the novel and unexpected discovery that theiodine/polymer complexes described herein are compatible withcyanoacrylate esters forming a prepolymer composition which, uponpolymerization, provides for an antimicrobial cyanoacrylate polymericfilm. Compatibility is assessed by the fact that these complexes aredispersible in the cyanoacrylate ester composition at antimicrobiallyeffective concentrations and when so employed, do not cause prematurepolymerization of the cyanoacrylate ester composition and do not preventeffective polymerization of the cyanoacrylate ester composition whenapplied to mammalian skin. Moreover, the polymerizable cyanoacrylateester composition comprising such complexes forms a flexible, durablepolymeric film having the complex incorporated therein which complex isreleased from the film in sufficient amounts to provide antimicrobialproperties to the film.

As shown in the examples below, many other conventional antimicrobialagents, when added to the cyanoacrylate ester composition causepolymerization of this composition as evidenced by gel formation within24 hours of such addition or, in the case of elemental iodine, preventin situ polymerization of the cyanoacrylate ester composition onmammalian skin. Accordingly, such agents are not compatible with thecyanoacrylate ester compositions.

The compositions of this invention are prepared by adding theiodine/polymer complex to the cyanoacrylate ester composition. Theiodine/polymer complex is preferably added as the commercially availablesolid composition rather than as the commercially available aqueous orethanolic solution insofar as the solution can cause prematurepolymerization of the cyanoacrylate ester which is apparently due tosolvent's effects. Accordingly, the compositions described herein arepreferably free of added solvents (e.g., water, organic solvents such aschloroform, methanol, ethanol, toluene, ethyl acetate, hexane, etc.).

Upon addition of the solid iodine/polymer complex to the cyanoacrylateprepolymer composition, the resulting system is thoroughly mixed toobtain a homogeneous suspension.

The amount of iodine/polymer complex added to the cyanoacrylatecomposition is a sufficient amount such that the resulting polymericfilm is antimicrobial. Preferably, from about 5 to about 40 weightpercent of the iodine/polymer complex and more preferably from about 10to 25 weight percent is added to the cyanoacrylate composition based onthe total weight of the composition.

The specific amount of iodine/polymer complex required to effectantimicrobial properties in the resulting polymeric film can be readilymeasured by conventional in vitro assays measuring zones of microbialgrowth inhibition around the film. Zones of inhibition of at least 1millimeter and preferably 3 millimeters from the edge of the film whentested in the manner of Example 2 below evidence that the polymeric filmis antimicrobial. Assessing the amount of iodine/polymer complexrequired in the polymeric film to effect such a zone of inhibition iswell within the skill of the art.

The composition of the antimicrobial complex and the cyanoacrylate estercan be formulated to a specific viscosity to meet disparate demands forthe intended application of the composition. For example, relatively lowviscosities are often preferred where application is to be made to alarge surface area (e.g., abdominal surfaces). This preference resultsfrom the fact that these forms are less viscous and, accordingly, willpermit more facile large surface area application of a thin film.Contrarily, where application is to be made to a specific position onthe skin (e.g., elbow surfaces, knee surfaces and the like), higherviscosity compositions, including those containing thixotropicmaterials, are preferred to prevent "running" of the compositions tounintended locations.

Accordingly, these compositions have a viscosity of from about 2 to50,000 centipoise at 20° C. For low viscosity applications, viscosityranges of from about 2 to 1,500 centipoise at 20° C. are preferred. Morepreferably, the cyanoacrylate ester employed in the composition isalmost entirely in monomeric form and the composition has a viscosity offrom about 5 to about 500 centipoise at 20° C.

A thickening agent is optionally employed to increase the viscosity ofthe composition which thickening agent is any biocompatible materialwhich increases the viscosity of the composition. Suitable thickeningagents include, by way of example, polymethyl methacrylate (PMMA) orother preformed polymers soluble or dispersible in the composition, asuspending agent such as fumed silica and the like, with PMMA beingpreferred. Fumed silica is particularly useful in producing a gel fortopical application having a viscosity of from about 1500 to 50,000.Suitable thickening agents for the cyanoacrylate compositions describedherein also include a polymer of the alkyl cyanoacrylate as disclosed inU.S. Pat. Nos. 3,654,239³ and 4,038,345¹⁶ both of which are incorporatedherein by reference in their entirety.

Thickening agents are deemed to be biocompatible if they are soluble ordispersible in the composition and are compatible with the skin asmeasured by the lack of moderate to severe skin irritation.

The cyanoacrylate composition preferably includes a biocompatibleplasticizer and such plasticizers are preferably included from about 10to 30 weight percent and more preferably from about 18 to 25 weightpercent based on the weight of the composition absent the antimicrobialagent. A particularly preferred biocompatible plasticizer for use in thecompositions described herein is dioctylphthalate.

Additionally, the cyanoacrylate compositions described herein preferablyinclude a polymerization inhibitor in an effective amount to inhibitpremature polymerization of the composition. In a particularly preferredembodiment, this inhibitor is sulfur dioxide which is employed at fromabout 50 to 500 ppm based on the total weight of the composition absentthe antimicrobial agent. Another preferred inhibitor is glacial aceticacid which is employed in an amount effective to inhibit prematurepolymerization.

The cyanoacrylate ester compositions may additionally contain one ormore optional additives such as colorants, perfumes, anti-diffusionagents, rubber modifiers, modifying agents, etc. In practice, each ofthese optional additives should be both miscible and compatible with thecyanoacrylate composition and the resulting polymer. Compatibleadditives are those that do not prevent the use of the cyanoacrylates inthe manner described herein.

In general, colorants are added so that the polymer layer formed on theskin will contain a discrete and discernable color. Perfumes are addedto provide a pleasant smell to the formulation. Rubber modifiers areadded to further enhance the flexibility of the resulting polymer layer.The amount of each of these optional additives employed in thecomposition is an amount necessary to achieve the desired effect.

Additionally, the cyanoacrylate composition can optionally comprise aformaldehyde scavenger compound such as those described by Leung, etal.²² The use of such scavengers has been suggested as enhancinginternal in vivo applications of cyanoacrylates.

Still further, it is contemplated that the cyanoacrylate composition canoptionally comprise an acrylic monomer that will act as a polymericplasticizer when it copolymerizes with the cyanoacrylate composition.²⁴

Utility

The methods described herein are useful in forming in situ a broadspectrum antimicrobial polymeric film on the skin surface of a mammalianpatient. Such mammalian patients preferably include humans as well as,for example, domestic animals such as horses, cows, dogs, sheep, cats,etc.

The polymeric film finds particular utility in inhibiting microbialcontamination thereunder and in the areas immediately adjacent thereto.Accordingly, such polymeric films can be used to topically cover smallnon-suturable wounds on skin surfaces which wounds do not penetratethrough the dermal layer of the skin as in the manner described inBarley, et al.⁴ When so employed, the antimicrobial cyanoacrylatecomposition is applied over the small non-suturable wound. Uponpolymerization, an antimicrobial polymeric film is formed over the woundwhich provides for broad spectrum antimicrobial properties at the woundsurface while also preventing exogenous contaminants from entering thewound.

Additionally, the polymeric films formed from the antimicrobialcyanoacrylate compositions described herein can also be used in the insitu formation of a surgical incise drape in the manner described byAskill, et al.¹¹. When so employed, the in situ formed film stronglyadheres to the mammalian skin surface to provide for a surgical incisedrape which does not lift during surgery and has broad spectrumantimicrobial properties.

When used as either a small wound covering or as a surgical incisedrape, the antimicrobial polymeric film will only adhere to the skin fora period of about 1-4 days after which time it sloughs off. This occursbecause the cyanoacrylate polymer adheres only to the uppermost portionof the epidermal layer which is continuously in the process of beingsloughed off and replaced by the underlying cells. Accordingly, theantimicrobial cyanoacrylate film need not be removed after in situformation. However, if removal of the polymeric film is required, suchcan be accomplished with a material such as acetone (nail polishremover).

Other utilities for the compositions of this invention include their useto form polymeric hemostatic films³, use to form polymeric films ininhibiting surface skin irritation arising from friction between theskin surface and artificial devices such as tapes, prosthetic devices,casts, etc.⁶, use in forming polymeric films in inhibiting acuteradiation-induced skin damage²³, and use in treating incontinence andareas adjacent to stomas.²⁵

Kits

In view of the many different uses for topical application ontomammalian skin, this invention also encompasses a kit of parts usefulfor applying the antimicrobial cyanoacrylate compositions describedherein onto mammalian skin. In particular, such a kit of parts comprises(a) a container comprising therein an antimicrobial prepolymericcomposition as described above and (b) an applicator means for applyingthe composition onto mammalian skin.

The container comprises any compatible material which stores thecyanoacrylate composition without degradation of the container orprematurely polymerizing the cyanoacrylate prepolymer. Such materialsinclude, by way of example, inorganic materials such as Type 1 glass(including amber glass), ceramics, metals (e.g., aluminum, tin and tincoated tubes), etc. and organic materials such as inert polymersincluding polyolefins (e.g., high density polyethylene), fluorinatedpolyolefins, and the like. Examples of suitable containers include thoserecited in Bolduc, U.S. Pat. No. 5,154,320, which is incorporated hereinby reference in it entirety.

Suitable applicator means include brushes, rollers, aerosols, swabs,foams (e.g., polyethylene foam) and the like. A particularly preferredapplicator is described in U.S. Pat. No. 4,183,684.

In one embodiment, the container and applicator means are combined intoa single article such as a brush affixed to the terminal portion of thecontainer wherein means are employed to prevent premature release of thecyanoacrylate prepolymeric composition. For example, the brush may beoverlayed with a removable imperable barrier. When application of thecyanoacrylate prepolymer composition is intended, the barrier is simplyremoved.

In another embodiment, the container and applicator means are separatearticles designed to mate with each other. For example, thecyanoacrylate prepolymer composition could be stored in an amber vialsealed with a screw cap and the applicator means includes a screwmechanism which mates with the screw mechanism on the top of the vial.When application of the cyanoacrylate prepolymer composition isintended, the cap is removed from the vial and the applicator isattached. The particular container/applicator means are not critical andother such means are well within the scope of the skilled artisanincluding those set forth by Bolduc, U.S. Pat. No. 5,154,320.

The following examples illustrate certain embodiments of the inventionbut are not meant to limit the scope of the claims in any way.

EXAMPLES

In the examples below, all temperatures are in degrees celsius (unlessotherwise indicated) and all percents are weight percent (also unlessotherwise indicated) except for percent inhibition which is truemathematical percentage. Additionally, the following abbreviations havethe following meanings. If an abbreviation is not defined, it has itsgenerally accepted meaning.

    ______________________________________                                        CFU      =         Colony forming units                                       conc.    =         concentration                                              flex.    =         flexibility                                                dur.     =         durability                                                 mL       =         milliliters                                                mm       =         millimeters                                                ppm      =         parts per million                                          PVP-I.sub.2                                                                            =         polyvinylpyrrolidone iodine complex                        SAB-DEX  =         Sabouraud Dextrose                                         TSA      =         trypticase soy agar                                        ______________________________________                                    

EXAMPLE 1

The following example examines the compatibility of differentantimicrobial agents in cyanoacrylate compositions. In particular, thecomposition employed monomeric n-butyl cyanoacrylate containing 100 ppmsulfur dioxide and 20 weight percent of dioctyl phthalate absent theantimicrobial agent. In each case, either 5 weight percent, 10 weightpercent or 20 weight percent of the antimicrobial agent, based on thetotal weight of the composition, was added thereto and the properties ofthe resulting composition measured. The antimicrobial agents tested wereelemental iodine, solid polyvinylpyrrolidone iodine, a 30% aqueoussolution of polyvinylpyrrolidone iodine, silver nitrate,hexachlorophene, merbromin, tetracycline.HCl, tetracycline hydrate, anderythromycin (each of these antimicrobial agents were obtained fromcommercial sources).

The evaluation included assessing whether the antimicrobial agent wassoluble or suspendable in the composition; whether the resultingcomposition cured upon contact with skin; whether curing provided for apolymeric film in situ on the skin; whether the polymeric film wasflexible and durable. Solubility and suspendability were determined byconventional standards. The ability of the resulting composition to curein situ upon application to skin was measured by applying thecyanoacrylate composition onto the upper arm of a male human subject anddetermining whether polymerization proceeded (up to 5 minutes) and, ifso, the time required for polymerization. Film forming capabilities onthe skin were assessed by visual evaluation. Durability was assessed bydetermining whether the film was retained on the skin surface for atleast 24 hours and flexibility was measured by the ability of the filmto be retained on the skin without cracking or peeling for at least 24hours. The results of this evaluation are summarized in Table I below:

                  TABLE I                                                         ______________________________________                                        Anti-                                                                         microbial                        Film                                         Agent   Conc.   Soluble   Curable                                                                              Formed                                                                              Flex.                                                                              Dur.                              ______________________________________                                        elemental                                                                             ˜20%                                                                            partially No     --    --   --                                iodine (I.sub.2)          (when                                                                         tested                                                                        for 5                                                                         minutes)                                            PVP-I.sub.2                                                                           10%     no        Yes    Yes   Yes  Yes                               solid           suspension.sup.2                                                                        (30                                                                           seconds)                                            PVP-I.sub.2                                                                           10%     no, gelled.sup.1                                                                        --     --    --   --                                solution                                                                      Silver  5%      no, gelled.sup.1                                                                        --     --    --   --                                nitrate                                                                       Hexachloro-                                                                           5%      no, gelled.sup.1                                                                        --     --    --   --                                phene                                                                         Merbromin                                                                             5%      no, gelled.sup.1                                                                        --     --    --   --                                tetracycline                                                                          5%      no, gelled.sup.1                                                                        --     --    --   --                                HCl                                                                           tetracycline                                                                          5%      no, gelled.sup.1                                                                        --     --    --   --                                hydrate                                                                       Erythro-                                                                              5%      no, gelled.sup.1                                                                        --     --    --   --                                mycin                                                                         ______________________________________                                    

¹ gel formation within 24 hours of addition of the antimicrobial agentevidences premature polymerization of the cyanoacrylate. In such cases,the antimicrobial agent initiates polymerization.

² the mixture is readily resuspended with mild agitation. No gel formedover an 8 week period when stored at room temperature.

The above data demonstrates that of the antimicrobial agents tested,only polyvinylpyrrolidone iodine complex was compatible with thecyanoacrylate composition and, of the polyvinylpyrrolidone iodinecomplexes tested, only the solid form was compatible. Evidently, thesolvent in the solution form of polyvinylpyrrolidone iodine complexinitiated polymerization of the cyanoacrylate. Significantly, thesuspension formed by the addition of solid polyvinylpyrrolidone iodinecomplex was curable in situ on human skin resulting in a flexible anddurable polymeric film.

In addition to the above, polyvinylpyrrolidone is a well knownbiocompatible polymer thereby evidencing that such polymers, whencompleted with iodine, are suitable for use in the compositionsdescribed herein.

EXAMPLE 2

The following example was conducted to determine whether sufficientpolyvinylpyrrolidone iodine complex was incorporated into the polymericcyanoacrylate film formed in situ to render this film antimicrobial.

A. Preparation of the Inoculum

Specifically, the surfaces of two TSA plates, 100×15 mm, were inoculatedwith stock cultures (maintained on TSA slants) with the followingmicroorganisms using a sterile inoculating loop: Staphylococcus aureus(ATCC No. 6538) and Staphylococcus epidermidis (ATCC No. 12228). Theplates were incubated at 30° to 35° C. for 24 hours. The surfaces of twoSAB-DEX agar plates were streaked with Candida albicans and incubated at20-25° C. for 48 hours.

The cultures were harvested with sterile saline. Each culture suspensionwas collected in a sterile container and sufficient sterile saline wasadded to reduce the microbial count to obtain a working suspension ofapproximately 1×10⁸ CFU's per mL.

The specific microorganisms recited above were selected for inclusionherein because they are common human skin pathogens (bacteria andfungus).

B. Inoculation of Plates

Each of the three test microorganisms was used to inoculate individualTSA plates by streaking them with sterile cotton tip applicatorssaturated with the appropriate suspension. The plates were allowed todry.

C. Inhibition Study

Films of polymerized n-butyl cyanoacrylate comprising 0%, 10%, 15%, 20%or 30% iodine polyvinylpyrrolidone complex were formed on 25 mm filterdisks and then cut into approximately 11 to 13 mm pieces. The pieceswere placed in the center of the appropriate inoculated TSA plates. Anuntreated filter disk was cut into half, and one-half was placed in thecenter of the appropriate inoculated TSA plate and the other one-halfwas place in the center of non-inoculated TSA plates, to serve as anegative control. Two inoculated plates of each microorganism were alsoused as positive controls without the test article. These plates werethen incubated for 3 days at 30° to 35° C. After incubation, the plateswere removed and examined for any signs of microbial growth inhibition.

The results of this analysis are set forth in Tables II-IV below. Thesample sizes reported are the portion of the sample actually in contactwith the agar. The sizes of the zone of inhibition include the diametersof the entire zone including the test article size.

                  TABLE II                                                        ______________________________________                                        Results for Staphylococcus aureus                                             SAMPLE:                    ZONE OF                                            n-butyl cyanoacrylate                                                                        SAMPLE SIZE.sup.1                                                                         INHIBITION.sup.1                                   comprising     (in mm)     (in mm)                                            ______________________________________                                        0% PVP-I.sub.2 12          12                                                 10% PVP-I.sub.2                                                                              12          15                                                 15% PVP-I.sub.2                                                                              12.5        14                                                 20% PVP-I.sub.2                                                                              11.5          15.5                                             30% PVP-I.sub.2                                                                              12.5        20                                                 Untreated Filter Disk                                                                        13.sup.2     13.sup.2                                          Negative Control                                                                             13.sup.2     13.sup.2                                          Positive Control                                                                             n/a          0                                                 ______________________________________                                    

                  TABLE III                                                       ______________________________________                                        Results for Staphylococcus epidermis                                          SAMPLE:                    ZONE OF                                            n-butyl cyanoacrylate                                                                        SAMPLE SIZE.sup.1                                                                         INHIBITION.sup.1                                   comprising     (in mm)     (in mm)                                            ______________________________________                                        0% PVP-I.sub.2 12          12                                                 10% PVP-I.sub.2                                                                                12.5      15                                                 15% PVP-I.sub.2                                                                              12          15.5                                               20% PVP-I.sub.2                                                                                12.5      20.5                                               30% PVP-I.sub.2                                                                              13          27.5                                               Untreated Filter Disk                                                                         13.sup.2   13.sup.2                                           Negative Control                                                                              13.sup.2   13.sup.2                                           Positive Control                                                                             n/a         0                                                  ______________________________________                                    

                  TABLE IV                                                        ______________________________________                                        Results for Candida albicans                                                  SAMPLE:                    ZONE OF                                            n-butyl cyanoacrylate                                                                        SAMPLE SIZE.sup.1                                                                         INHIBITION.sup.1                                   comprising     (in mm)     (in mm)                                            ______________________________________                                        0% PVP-I.sub.2 12          12                                                 10% PVP-I.sub.2                                                                              12.5        18.5                                               15% PVP-I.sub.2                                                                              12.5        23                                                 20% PVP-I.sub.2                                                                              12.5        20.5                                               30% PVP-I.sub.2                                                                              13          29.5                                               Untreated Filter Disk                                                                        13.sup.2    13.sup.2                                           Negative Control                                                                             13.sup.2    13.sup.2                                           Positive Control                                                                             n/a         0                                                  ______________________________________                                         .sup.1 average of two runs                                                    .sup.2 single run only                                                   

The above data demonstrates that the compositions of this inventionproduce a polymeric cyanoacrylate film which have broad spectrum ofantimicrobial activity. Based on these results, it is expected thatthese compositions would be antimicrobial when formed in situ onmammalian skin surfaces.

From the foregoing description, various modifications and changes in thecomposition and method will occur to those skilled in the art. All suchmodifications coming within the scope of the appended claims areintended to be included therein.

What is claimed is:
 1. A kit of parts comprising:(a) a containercomprising therein an antimicrobial prepolymeric composition whichcomprises a mixture of:(i) a polymerizable cyanoacrylate ester; and (ii)an antimicrobially effective amount of a complex of iodine moleculeswith a biocompatible polymer;wherein said composition is capable offorming a film on mammalian skin surfaces; and (b) an applicator meansfor applying the composition onto mammalian skin.
 2. A kit of partsaccording to claim 1 wherein the container and applicator means arecombined into a single article.
 3. A kit of parts according to claim 1wherein the container and applicator means are separate articles.
 4. Thekit of according to claim 1 wherein the polymerizable cyanoacrylateester is a polymerizable monomer or oligomer of a cyanoacrylate esterwhich, in monomeric form, is represented by formula I: ##STR4## whereinR is selected from the group consisting of: alkyl of 1 to 10 carbonatoms,alkenyl of 2 to 10 carbon atoms, cycloalkyl groups of from 5 to 8carbon atoms, phenyl, 2-ethoxyethyl, 3-methoxybutyl, and a substituentof the formula: ##STR5## wherein each R' is independently selected fromthe group consisting of: hydrogen and methyl, andR" is selected from thegroup consisting of: alkyl of from 1 to 6 carbon atoms, alkenyl of from2 to 6 carbon atoms, alkynyl of from 2 to 6 carbon atoms, cycloalkyl offrom 3 to 8 carbon atoms, aralkyl selected from the group consisting ofbenzyl, methylbenzyl and phenylethyl, phenyl, and phenyl substitutedwith 1 to 3 substituents selected from the group consisting of hydroxy,chloro, bromo, nitro, alkyl of 1 to 4 carbon atoms, and alkoxy of from 1to 4 carbon atoms.
 5. The kit of parts according to claim 1 wherein R isalkyl of from 4 to 10 carbon atoms.
 6. The kit of parts according toclaim 5 wherein R is alkyl of from 4 to 8 carbon atoms.
 7. The kit ofparts according to claim 6 wherein R is selected from the groupconsisting of butyl, pentyl or octyl.
 8. The kit of parts according toclaim 7 wherein R is n-butyl.
 9. The kit of parts according to claim 1wherein said complex of iodine molecules with a biocompatible polymer ispolyvinylpyrrolidone iodine.
 10. The kit of parts according to claim 1wherein said antimicrobial prepolymeric composition further comprises abiocompatible plasticizer.
 11. The kit of parts according to claim 10wherein said biocompatible plasticizer is dioctyl phthalate or acetyltri-n-butyl citrate.
 12. The kit of parts according to claim 1 whereinsaid antimicrobial prepolymeric composition further comprises apolymerization inhibitor.
 13. The kit of parts according to claim 12wherein said polymerization inhibitor is SO₂.
 14. The kit of partsaccording to claim 1 herein said antimicrobial prepolymeric compositioncomprises:(a) a polymerizable cyanoacrylate ester which, in monomericform, is represented by formula II: ##STR6## (b) an antimicrobiallyeffective amount of polyvinylpyrrolidone iodine complex.
 15. The kit ofparts according to claim 14 wherein said antimicrobial prepolymericcomposition further comprises a biocompatible plasticizer.
 16. The kitof parts according to claim 15 wherein said biocompatible plasticizer isdioctyl phthalate or acetyl tri-n-butyl citrate.
 17. The kit of partsaccording to claim 14 wherein said antimicrobial prepolymericcomposition further comprises a polymerization inhibitor.
 18. The kit ofparts according to claim 17 wherein said polymerization inhibitor isSO₂.